title: DeepSAGE reveals genetic variants associated with alternative polyadenylation and expression of coding and non-coding transcripts.
abstract: Many disease-associated variants affect gene expression levels (expression quantitative trait loci, eQTLs) and expression profiling using next generation sequencing (NGS) technology is a powerful way to detect these eQTLs. We analyzed 94 total blood samples from healthy volunteers with DeepSAGE to gain specific insight into how genetic variants affect the expression of genes and lengths of 3'-untranslated regions (3'-UTRs). We detected previously unknown cis-eQTL effects for GWAS hits in disease- and physiology-associated traits. Apart from cis-eQTLs that are typically easily identifiable using microarrays or RNA-sequencing, DeepSAGE also revealed many cis-eQTLs for antisense and other non-coding transcripts, often in genomic regions containing retrotransposon-derived elements. We also identified and confirmed SNPs that affect the usage of alternative polyadenylation sites, thereby potentially influencing the stability of messenger RNAs (mRNA). We then combined the power of RNA-sequencing with DeepSAGE by performing a meta-analysis of three datasets, leading to the identification of many more cis-eQTLs. Our results indicate that DeepSAGE data is useful for eQTL mapping of known and unknown transcripts, and for identifying SNPs that affect alternative polyadenylation. Because of the inherent differences between DeepSAGE and RNA-sequencing, our complementary, integrative approach leads to greater insight into the molecular consequences of many disease-associated variants.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Zhernakova
authors.forename: Eleonora
authors.initials: E
authors.lastname: de Klerk
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.forename: Anastasios
authors.initials: A
authors.lastname: Mastrokolias
authors.forename: Shoaib
authors.initials: S
authors.lastname: Amini
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Ariyurek
authors.forename: Rick
authors.initials: R
authors.lastname: Jansen
authors.forename: Brenda W
authors.initials: BW
authors.lastname: Penninx
authors.forename: Jouke J
authors.initials: JJ
authors.lastname: Hottenga
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.forename: Eco J
authors.initials: EJ
authors.lastname: de Geus
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: Gert-Jan B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D026723:Polyadenylation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D018626:Retroelements / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D018626:Retroelements